The antiphospholipid syndrome (APS), characterized by thrombosis and pregnancy loss that occurs in the presence of antiphospholipid (aPL) antibodies, is a leading cause of miscarriage and maternal and fetal morbidity. Pregnancy complications in women with APS include fetal death, preeclampsia, and intrauterine growth restriction (IUGR). The pathogenic mechanisms that lead to injury in vivo are incompletely understood and the therapy for pregnant women with APS is only partially successful. Our studies in a murine model of APS, induced by passive transfer of human Apl antibodies, indicate that complement activation plays an essential and causative role in fetal loss and growth restriction. In addition, treatment with heparin, the standard therapy for pregnant patients with APS, prevents complement activation and protects mice from pregnancy complications induced by aPL antibodies, while anticoagulants that do not inhibit complement do not protect pregnancies. These studies indicate that APS is an inflammatory disease and, they suggest that complement inhibitory therapy might be an effective treatment. Our overall goals are to use the murine model of APS to determine how complement is activated, which complement products mediate the clinical complications associated with aPL antibodies, and the relative role of complement activation within the overall inflammatory cascade. In addition, we propose to test the hypothesis that activation of complement at the maternal-fetal interface plays an etiologic role in IUGR. Accordingly, our aims are: Aim 1. To determine which complement components and receptors are necessary or sufficient to mediate aPL antibody-induced placental injury, fetal loss and/or IUGR. (a) To identify the pathways that initiate complement activation and lead(s) to complement deposition in deciduas and poor pregnancy outcomes; (b) To identify the complement activation products and receptors that mediate fetal injury; (c) To assess the role of murine complement regulatory proteins in the control of local complement activation. Aim 2. To define the role of aPL antibody-mediated complement activation within the overall inflammatory cascade in order to identify complement-dependent vs. complement-independent mechanisms, (a) To define the contribution of Fc?R to aPL antibody-mediated injury; (b) To define the cellular and cytokine mediators which contribute to complement activation in deciduas, to IUGR and to fetal loss. The proposed study, together with our ongoing work to define the role of complement and cytokines in pregnancy complications in APS patients, will provide insights into the mechanisms by which complement induces disease and define targets for interventions to prevent aPL antibody-associated fetal demise and IUGR. Additionally, understanding how aPL antibodies "cause" pregnancy loss may translate into new concepts about maternal-fetal tolerance and miscarriages in general and benefit women with non-aPL-related pregnancy complications.